The immunogenetic regulation of the T-macrophage interaction in T helper cell induction will be investigated. This is a main step in the immunobiology of antibody formation. The key components of this interaction, the genetically related macrohpage factor 'GRF' a complex of Ia antigen and a fragment of immunogen released by macrophages, and its receptor on T cells will be further investigated. Biochemical analysis of GRF will include characterization of the Ia component, of the antigen fragment, and the link between these. Characterization of the receptor for GRF will focus on its immunochemical nature and whether there is a single receptor for both components, or two receptors, this being a key question in the biology of T cell function. The receptor-GRF interaction involves 2 genes mapping in the I region of the H-2 complex. Thus the question of whether Immune response (Ir) genes are involved in this reaction will be tested, using synthetic polypeptide antigens which are known to be under Ir gene control. This system will be used to ascertain whether T cells use 1 or 2 receptors for recognizing GRF, by using antisera which react against receptors, such as anti-idiotype antisera. The mechanism of the genetic restriction of T-macrophage interaction will be analysed by using various types of irradiation chimeras, where T cells from parent or F1 tolerant to one or two H-2 types may be tested for their capacity to interact with various macrophages. Rather than using synthetic polypeptides for all this work, insulin, an antigen under Ir gene control and of biological importance in diabetes will also be used. The genetic control of the response to insulin will be analysed in vitro. Since it is possible to induce human helper T cells in vitro, the T-macrophage interaction will be investigated in vitro, to verify whether the principles outlined in the mouse can be generalized.